Immune responses must be tightly regulated to avoid hyporesponsiveness on one hand or excessive inflammation and the development of autoimmunity (hyperresponsiveness) on the other. This balance is at least partially attained through the throttling of activating signals by inhibitory signals. This ideally leads to an adequate immune response against an invader without excessive and extended inflammatory signals that promote the development of autoimmunity. The CD94NKG2 family of receptors is composed of members with activating or inhibitory potential. These receptors are expressed predominantly on NK cells and a subset of CD8 T cells, and they have been shown to play an important role in regulating responses against infected and tumorigenic cells. Our studies explore all aspects of the biology of these receptors, including ligand and receptor interaction, signaling, membrane dynamics, and regulation of gene expression.Our current emphasis is to understand, at the cell biology and molecular levels, how the the CD94NKGA inhibitory receptor inactivates signals generated by activation receptors in a dominating manner and by what mechanism this receptor traffics so as to maintain constant presence on the cell surface. [unreadable] The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94NKG2A is an ITIM containing inhibitory receptor expressed by NK cells and some CD8 T cells that recognizes HLAE. We showed that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94NKG2A engagement leads to recruitment and activation of src homology 2 domain bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrinradixinmoesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrinradixinmoesin phosphorylation. Thus, CD94NKG2A prevents actin dependent recruitment of raft associated activation receptors complexes to the activating synapse. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.